Inhibition of extracellular matrix synthesis by antisense compounds directed to nuclear proto-oncogenes

• US 6,133,242 A
• Filed: 06/05/1995
• Issued: 10/17/2000
• Est. Priority Date: 10/15/1993
• Status: Expired due to Fees

• Current Assignee: Thomas Jefferson University (Main Line Health System)
• Original Assignee: Thomas Jefferson University (Main Line Health System)
• Inventors: Shi, Yi, Zalewski, Andrew
• Primary Examiner(s): Brusca, John S.
• Assistant Examiner(s): McGarry, Sean
• Application Number:
  US08/461,366
• Time in Patent Office: 1,961 Days
• Field of Search: 435/6, 435/91.1, 435/172.1, 435/240.2, 435/455, 435/375, 435/325, 514/44, 536/23.1, 536/24.5, 536/24.1
• US Class Current: 514/44.00A
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C12N 15/1135 against oncogenes or tumor suppressor genes
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification

Abstract

A method and compounds are provided for inhibiting the synthesis of extracellular matrix proteins. Compounds of the invention comprise antisense oligonucleotides specific for nuclear proto-oncogenes. Preferably, antisense compounds of the invention are selected from the group consisting of c-myc and c-myb and are locally administered. The invention finds use in the treatment of a variety of disorders, including sclerotic disorders and restenosis, associated with the inappropriate synthesis of extracellular matrix proteins, particularly collagen.

Claims

1. A method of inhibiting or reducing scar formation in a tissue of an internal organ of a mammal, other than vascular tissue, the method comprising locally administering to said tissue one or more antisense oligonucleotides specific for c-myc in an amount effective to inhibit or decrease extracellular matrix protein formation.

2. The method of claim 1 wherein said extracellular matrix protein comprises collagen.

24. The method of claim 1 wherein the tissue comprises gastrointestinal organ tissue, or comprises biliary duct, lung, liver, ureter, urethra or bladder tissue.

3. A method of inhibiting or reducing scar formation in the skin of a mammal comprising locally administering to tissue of said skin one or more antisense oligonucleotides specific for c-myc in an amount effective to inhibit or decrease extracellular matrix protein formation in said tissue.

4. The method of claim 3 wherein said antisense oligonucleotide is administered topically.

5. A method of inhibiting the synthesis of extracellular matrix proteins in a tissue of an internal organ of a mammal, other than vascular tissue, the method comprising locally administering to said tissue one or more antisense oligonucleotides specific for c-myc in an amount effective to inhibit or decrease extracellular matrix protein formation.

6. The method of claim 5 wherein said extracellular matrix protein comprises collagen.

7. The method of claim 5 wherein said extracellular matrix protein comprises procollagen I or pro collagen III.

8. The method of claim 5 wherein said antisense oligonucleotide is complementary to the translation initiation region of c-myc mRNA.

9. The method of claim 5 wherein said antisense oligonucleotide has a length within the range of from 12 to 40 nucleotides.

10. The method of claim 9 wherein said antisense oligonucleotide has a length within the range of from 15 to 30 nucleotides.

11. The method of claim 5 wherein said antisense oligonucleotide comprises at least one modified nucleotide.

12. The method of claim 11 wherein the antisense oligonucleotide is a phosphorothioate antisense oligonucleotide.

13. The method of claim 9 wherein said antisense oligonucleotide has a sequence selected from the group of sequences consisting of SEQ ID NO:

1, SEQ ID NO;

6 and SEQ ID NO;

7.

14. The method of claim 13 wherein said antisense oligonucleotide has the sequence SEQ ID NO:

1.

15. The method of claim 13 wherein the antisense oligonucleotide is a phosphorothioate antisense oligonucleotide.

18. The method of claim 5 wherein said tissue is connective tissue.

19. The method of claim 18 wherein said local administration comprises delivery to connective tissue using a rigid, noncollapsable channel.

20. The method of claim 18 wherein said local administration comprises delivery to human connective tissue using iontophoresis to release said antisense oligonucleotide.

21. The method of claim 5 wherein said local administration comprises delivery with a catheter or a coated stent.

22. The method of claim 5 wherein said local administration comprises using a biodegradable polymer, non-biodegradable polymer or stent to release said antisense oligonucleotide.

23. The method of claim 5 further comprising administering a therapeutically effective amount of one or more antisense oligonucleotides specific for c-myb.

25. The method of claim 5 wherein the tissue comprises gastrointestinal organ tissue, or comprises biliary duct, lung, liver, ureter, urethra or bladder tissue.

16. A method of inhibiting the synthesis of extracellular matrix proteins in a tissue comprising skin fibroblasts comprising locally administering to said tissue one or more antisense oligonucleotides specific for c-myc in an amount effective to inhibit or decrease extracellular matrix protein formation.

17. The method of claim 16 wherein said antisense oligonucleotide is administered topically.